GluR-A-deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal.

Acquisition and reversal of a spatial discrimination were assessed in an appetitive, elevated plus-maze task in 4 groups of mice: knockout mice lacking the AMPA receptor subunit GluR-A (GluR1), wild-type controls, mice with cytotoxic hippocampal lesions, and controls that had undergone sham surgery. In agreement with previous studies using tasks such as the water maze, GluR-A-/- mice were unimpaired during acquisition of the spatial discrimination task, whereas performance in the hippocampal group remained at chance levels. In contrast to their performance during acquisition, the GluR-A-/- mice displayed a mild deficit during reversal of the spatial discrimination and were profoundly impaired during discrete trial, rewarded-alternation testing on the elevated T maze. The latter result suggests a short-term. flexible spatial working memory impairment in GluR-A-/- mice, which might also underlie their mild deficit during spatial reversal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory.

Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

GluR-A-dependent synaptic plasticity is required for the temporal encoding of nonspatial information.

Four related experiments studied operant performance of mice on differential reinforcement of low rates of responding (DRL) paradigms. Experiment 1 showed that excitotoxic hippocampal lesions impaired performance of a 10-s DRL schedule (DRL-10). Experiments 2 and 3 showed that GluR-A AMPA receptor subunit knockout mice, which are deficient in CA3-CA1 long-term potentiation (LTP), were markedly impaired at 15 s (DRL-15), but less impaired at DRL-10. Experiment 4 compared DRL-15 performance in mice from the 2 strains from which the GluR-A colony was derived and showed that they did not differ. The results show that GluR-A-containing AMPA receptors are required for normal performance on hippocampus-dependent, nonspatial working memory tasks, consistent with a role for GluR-A in the temporal encoding (what happened when) of nonspatial information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Altered ingestive behavior, weight changes, and intact olfactory sense in an APP overexpression model.

Transgenic APP23 mice were generated to model Alzheimer's disease. The APP23 model develops pathological features, learning deficits, and memory deficits analogous to dementing patients. In this report, transgenic mice exhibited several behavioral disturbances indicating the presence of neuropsychiatric symptoms of dementia. Aiming to verify whether the model also develops other behavioral problems, the authors investigated ingestive behavior in APP23 males of 3, 6 and 12 months. In addition, body weights of a naive male group were longitudinally monitored starting at weaning. Olfactory acuity was evaluated in mice of different age groups. Although olfactory functioning of APP23 mice appeared intact, they drank more and took more food pellets compared with wild-type littermates during a 1-week registration period. From the age of 4.5 weeks onward, APP23 males weighed significantly less than their control littermates, whereas this difference became more prominent with increasing age. Our results suggest the presence of a hypermetabolic state in this model. This is the first report, evidencing the presence of changes in eating and drinking behavior in a single transgenic Alzheimer mouse model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD.

Attention deficit hyperactivity disorder (ADHD) comprises a deficit in behavioral inhibition. A theoretical model is constructed that links inhibition to 4 executive neuropsychological functions that appear to depend on it for their effective execution: (a) working memory, (b) self-regulation of affect–motivation–arousal, (c) internalization of speech, and (d) reconstitution (behavioral analysis and synthesis). Extended to ADHD, the model predicts that ADHD should be associated with secondary impairments in these 4 executive abilities and the motor control they afford. The author reviews evidence for each of these domains of functioning and finds it to be strongest for deficits in behavioral inhibitions, working memory, regulation of motivation, and motor control in those with ADHD. Although the model is promising as a potential theory of self-control and ADHD, far more research is required to evaluate its merits and the many predictions it makes about ADHD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The cognitive enhancer T-588 partially compensates the motor associative learning impairments induced by scopolamine injection in mice.

The authors studied the effects of T-588 on scopolamine-induced memory impairments in the acquisition of a classical eyeblink conditioning in behaving adult mice. Mice injected with 0.3 mg/kg of scopolamine showed a marked deficit, compared with nontreated mice, in the acquisition of classical eyeblink conditioning using a trace paradigm. Coadministration of T-588 (0.05% wt/vol, in water) with scopolamine (0.3 mg/kg) significantly prevented this deficit in associative learning. To further assess the effects of T-588 on motor coordination and the cognitive deficits induced by scopolamine, the authors compared adult controls or scopolamine-treated mice in different behavioral tasks: rotarod, object recognition, passive avoidance, and prepulse inhibition. In all of these tasks, the authors found a significant impairment in the motor or cognitive abilities in scopolamine-injected mice, compared with controls. In addition, the coadministration of T-588 with scopolamine restored deficits induced by scopolamine alone. Importantly, the administration of T-588 alone did not evoke any change compared with values obtained for controls. These results suggest that T-588 could be used as a pharmacological agent to improve motor and associative learning disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The "Swedish" mutation of the amyloid precursor protein (APPswe) dissociates components of object-location memory in aged Tg2576 mice.

Aged Tg2576 mice show abnormalities in hippocampal morphology and physiology and display behavioral deficits in spatial navigation tasks consonant with a deficit in the functional properties of the hippocampus. However, the nature of the spatial representations disrupted by the "Swedish" mutation of the amyloid precursor protein (APPswe) is unclear. In an effort to characterize the memory deficits in Tg2576 mice, the spontaneous object exploration paradigm was used to interrogate spatial and object memory in mice. With object arrays of comparable size, 16-month-old Tg2576 mice showed a normal object familiarity/novelty effect but impaired memory for the location of objects when 2 objects exchanged locations (topological transformation; Experiment 1). In contrast, Tg2576 mice showed preferential exploration of familiar objects when they were moved to previously unoccupied locations (Experiment 2), irrespective of whether the transformation altered the metric properties of the object array (Experiments 3). These results suggest that Tg2576 mice are able to form representations of the identity of objects and a memory of the spatial organization of objects in an arena. In contrast, conjunctive memory for specific object-location associations is severely impaired in aged Tg2576 mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Altered performance of reelin-receptor ApoER2 deficient mice on spatial tasks using the Barnes maze.

The apolipoprotein E receptor 2 (ApoER2), expressed predominantly in forebrain regions including the hippocampus, is 1 of 2 receptors for the extracellular matrix protein reelin, which is critical for cortical development. Previous studies of ApoER2 mutant mice have indicated deficits in synaptic plasticity and learning. The current authors assessed learning and memory of ApoER2 knockout and wild-type mice on the Barnes circular maze. Mice were trained in this task for 22 days, followed by memory recall and reversal tests. ApoER2 knockout mice were initially slower to complete the task, but by Day 22 they were more accurate than wild-type mice on several indices. There were no differences in memory assessed by the recall task, but ApoER2 knockout mice performed significantly worse on the memory reversal task. ApoER2 knockout mice also displayed altered use of specific search strategies and relationship of these strategies to errors made on the maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced CaMKII activity and spatial cognitive function in SAMP6 mice.

Senescence-accelerated mouse prone 6 (SAMP6) mice exhibit increased expression of NMDA receptor NR2B subunit (NR2B) and improved short-term memory compared with senescence-accelerated mouse resistance 1 (SAMR1) mice. The Thr286 phosphorylation of alpha calcium/calmodulin-dependent protein kinase II (CaMKII) has a crucial role in plasticity and learning among multiple downstream signaling pathways linked to the NMDA receptor. To examine the relationship between CaMKII activity and spatial learning in SAMP6, the authors employed western blot analysis and behavioral analyses (object location and delayed spatial win-shift eight-arm radial-maze tests). The levels of Thr286 and Ser831 phosphorylation of CaMKII and AMPA receptor subunit glutamate receptor 1 (CaMKII substrate), respectively, were increased in hippocampus of SAMP6 compared with SAMR1. SAMP6 showed faster hippocampal-dependent spatial memory formation than SAMR1 in both the object location and win-shift eight-arm radial-maze tests. Our results indicate that increased CaMKII activity influences the NR2B/CaMKII signal pathway and cognitive function in SAMP6. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related deficits in mice performing working memory tasks in a water maze.

This study determined whether mice exhibit spatial working memory deficits with increased age. C57BL/6JNia mice of 3 different ages were tested in the Morris water maze with 2 protocols designed to assess immediate and delayed working memory abilities. Young mice required multiple trials in order to show improvements in the working memory task. Deficits in immediate working memory were detected in both 10- and 24- to 26-month-old mice. Reference memory deficits and declines in performance in the delayed working memory task were only seen in 24- to 26-month-olds. This increased susceptibility of immediate working memory processes to the aging process in mice may be related to their need for more rehearsal in the water maze than other species. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral Phenotype of the Reeler Mutant Mouse: Effects of Reln Gene Dosage and Social Isolation.

Reeler (rl/rl) and reeler/wild-type (+/rl) mice synthesize Reln at subnormal rates, as do patients with schizophrenia, bipolar disorder, and autism, thereby forming the basis for a Reln hypothesis for vulnerability to these psychopathologies and justifying attention to the behavioral phenotypes of Reln-deficient mice. Tests of gait, emotionality, social aggression, spatial working memory, novel-object detection, fear conditioning, and sensorimotor reflex modulation revealed the behavioral phenotype of rl/rl, but not +/rl, mice to be different from that of wild-type (+/+) mice. These results reveal no effect of Reln gene dosage and provide significant challenges to both the Reln and the neurodevelopmental hypotheses of the etiology of major psychopathologies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial learning deficits in mice with a targeted glucocorticoid receptor gene disruption

Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor-mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor.     

Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone.

C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed. Mice exposed to CPZ for 2 and 3 weeks displayed more climbing behavior and lower prepulse inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neocortical ectopias in BXSB mice: effects upon reference and working memory systems

BXSB mice have an approximately 40-60% incidence of neocortical ectopias in layer I of the prefrontal/motor cortex. Prior studies have found major behavioral differences between those with ectopias and their non-ectopic littermates. Some of these findings indicate that the two groups differ with respect to spatial reference and working memory. The purpose of this study was to measure reference and working memory in the same animals to test the hypothesis that the ectopics would have better reference memory but less effective working memory. The Lashley III maze has cul-de-sacs which must be eliminated, and T-choices where the animal has to decide whether to go left or right. Ectopic and non-ectopic mice were equally able to learn the maze and did not differ on cul-entry or T-choice errors. Then the maze was inverted and the animals were retested. Turning the maze upside down did not change the relative status of the blind alleys. Therefore, the reference memory knowledge from the prior week's training could be used to avoid entering the culs. However, inverting the maze caused a left-right mirror image reversal of the T-choices. Therefore, prior reference memory information would interfere with learning the new path through the maze, whereas working memory would enable the mouse to eliminate T-choice errors. Ectopic mice made less cul-entry errors and more T-choice errors than their non-ectopic littermates, as predicted.     

Medial septal lesions disrupt spatial, but not nonspatial, working memory in rats.

In Exp 1, rats with small medial septal lesions were less able than were control rats to remember the location of the arm of a Y maze they had been forced to enter on the preceding sample run. Moreover, as the retention interval between the sample and choice runs on this spatial delayed nonmatching-to-sample (DNMTS) task was increased to 1 and 2 min, the magnitude of the deficit increased. In contrast, these same lesioned rats were not deficient in Exp 2 in their ability to remember the object they had encountered in the straight alley on the sample run. In fact, when the retention interval was increased to 1 min on this nonspatial DNMTS task, the rats with medial septal lesions were more accurate than were the controls. This pattern of results did not appear to be due to task difficulty, recovery of function, or sequence of training. Rather, these results indicate that damage to the septohippocampal system disrupts spatial working memory more than it disrupts nonspatial working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Similarities and differences in spatial learning and object recognition between young male C57Bl/6J mice and Sprague-Dawley rats.

Mice and rats are often used interchangeably in neuroscience research. However, species differences in brain structure and connectivity exist within the medial temporal lobe circuits that contribute to learning and memory. The hippocampus in particular contributes to both spatial learning and recognition memory, but the extent to which rats and mice are comparable in these two cognitive domains remains unclear. To evaluate potential species differences in spatial memory and object recognition, young adult male Sprague–Dawley rats and male C57Bl/6J mice were tested in the water maze and novel object recognition tasks. Following six days of training, with four trials per day, there was no difference in the ability of rats and mice to learn the location of a hidden platform. However, rats performed better than mice on the probe trial, indicative of superior retention. In the novel object preference test, no species differences in recognition memory were detected, although rats spent more time exploring the arena and took longer to approach the objects. These observations suggest that while species differences in spatial memory retention are present, they do not correlate with differences in object recognition memory. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression.

Evidence suggests that brain-derived neurotrophic factor (BDNF) may be important in the pathophysiology of depression, in addition to its role as a neurotrophic factor for sensory neurons. The authors conducted a series of experiments examining the behavioral profile of BDNF heterozygous knockout and wild-type mice. The heterozygous and wild-type mice did not differ on measures of activity, exploration, or hedonic sensitivity, or in the forced swim test. When assessed in the learned helplessness paradigm, heterozygous mice were slower to escape after training than were wild-type mice (p?=?.02). This effect may be accounted for by the fact that these mice demonstrate a reduced sensitivity to centrally mediated pain, apparent on the hot plate and Formalin injection tests of nociception. Overall, heterozygous mice were not more likely to display anxious or depressive-like behaviors and, consequently, may not constitute a murine model of genetic vulnerability to mood and anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired "episodic-like" object memory in adult APPswe transgenic mice.

An early clinical symptom of Alzheimer's disease is impaired episodic memory. However, the precise pathological event(s) that underpins this deficit remains unclear. In the present study, the authors examined whether wild-type mice and Tg2576 mice expressing an amyloid precursor protein (APP) mutation are able to form an integrated memory of the spatio-temporal context in which objects are presented. In Experiment 1, wild-type mice, but not Tg2576 mice that were 10-12 months old, explored objects presented in a novel location. In Experiment 2, wild-type mice explored an object that was presented both earlier in a sequence and in a different location relative to other objects that possessed only one of these properties (i.e., memory for "what," "where," and "when" items were presented). In contrast, the behavior of adult Tg2576 mice was influenced only by the temporal order in which objects were presented. These results demonstrate that wild-type, but not APP-mutant, mice are able to form an "episodic-like" memory of the spatio-temporal properties of objects and support the hypothesis that aberrant APP processing contributes to impairments in event memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disentangling the adult attention-deficit hyperactivity disorder endophenotype: Parametric measurement of attention.

Attention deficit hyperactivity disorder (ADHD) persists frequently into adulthood. The decomposition of endophenotypes by means of experimental neuro-cognitive assessment has the potential to improve diagnostic assessment, evaluation of treatment response, and disentanglement of genetic and environmental influences. We assessed four parameters of attentional capacity and selectivity derived from simple psychophysical tasks (verbal report of briefly presented letter displays) and based on a “theory of visual attention.” These parameters are mathematically independent, quantitative measures, and previous studies have shown that they are highly sensitive for subtle attention deficits. Potential reductions of attentional capacity, that is, of perceptual processing speed and working memory storage capacity, were assessed with a whole report paradigm. Furthermore, possible pathologies of attentional selectivity, that is, selection of task-relevant information and bias in the spatial distribution of attention, were measured with a partial report paradigm. A group of 30 unmedicated adult ADHD patients and a group of 30 demographically matched healthy controls were tested. ADHD patients showed significant reductions of working memory storage capacity of a moderate to large effect size. Perceptual processing speed, task-based, and spatial selection were unaffected. The results imply a working memory deficit as an important source of behavioral impairments. The theory of visual attention parameter working memory storage capacity might constitute a quantifiable and testable endophenotype of ADHD. (PsycINFO Database Record (c) 2011 APA, all rights reserved)